ABSTRACT Investigators have long suspected that pathogenic microbes might contribute to the onset or progression of Alzheimer's disease (AD) although findings have been inconclusive, with reports of microbe-related antigens from entities as diverse as herpesviruses and borrelia species. Recent large-scale efforts such as the NIH Accelerating Medicines Partnership for Alzheimer's disease (AMP-AD) are generating multiple forms of next- generation sequencing data on large, well-characterized AD cohorts and controls. These data present new opportunities to detect the presence of viral species directly from clinical samples and to put measures of viral species abundance into the context of the most molecular networks and clinical features. We plan to build upon our preliminary work that has identified consistently increased abundance of specific Herpesviridae species in post mortem brain tissue from individuals with AD, and demonstrated viral regulation of AD associated molecular, genetic and clinic-pathological networks. The Aims of this proposal are designed to illuminate the genetic, transcriptomic and proteomic host networks that confer cognitive and neuropathological resilience to these AD- associated viral species, with the goal of identifying novel therapeutic opportunities for the treatment of AD. This requires that we systematically characterize the impact of viral perturbations that are known or suspected to associate with a diagnosis of AD, amyloid plaque density, neurofibrillary tangle severity or clinical dementia ratings, and identify the host networks capable of modifying these relationships. By modelling the causal interactions that relate virus, host and disease, we can conceptualize these host molecules (and their appropriate perturbations) as potential mediators of resilience in the face of viral infection. We will validate genetic and small molecule perturbations of virally infected cerebral organoids systems, monitoring changes in resilience to viral infectivity, AD associated neuropathology markers, and host transcriptomics, including activity of targeted resilience networks. The expected outcome of this study is to identify and evaluate specific host molecular networks and small molecules that are capable of modulating host responses to infection with AD-relevant viruses.